Copper‐Single‐Atom Coordinated Nanotherapeutics for Enhanced Sonothermal‐Parallel Catalytic Synergistic Cancer Therapy

Abstract Phototherapy and sonotherapy are recognized by scientific medicine as effective strategies for treating certain cancers. However, these strategies have limitations such as an inability to penetrate deeper tissues and overcome the antioxidant tumor microenvironment. In this study, a novel “BH” interfacial‐confined coordination strategy to synthesize hyaluronic acid‐functionalized single copper atoms dispersed over boron imidazolate framework‐derived nanocubes (HA‐NC_Cu) to achieve sonothermal–catalytic synergistic therapy is reported. Notably, HA‐NC_Cu demonstrates exceptional sonothermal conversion performance under low‐intensity ultrasound irradiation, attained through intermolecular lattice vibrations. In addition, it shows promise as an efficient biocatalyst, able to generate high‐toxicity hydroxyl radicals in response to tumor‐endogenous hydrogen peroxide and glutathione. Density functional theory calculations reveal that the superior parallel catalytic performance of HA‐NC_Cu originates from the CuN 4 C/B active sites. Both in vitro and in vivo evaluations consistently demonstrate that the sonothermal–catalytic synergistic strategy significantly improves tumor inhibition rate (86.9%) and long‐term survival rate (100%). In combination with low‐intensity ultrasound irradiation, HA‐NC_Cu triggers a dual death pathway of apoptosis and ferroptosis in MDA‐MB‐231 breast cancer cells, comprehensively limiting primary triple‐negative breast cancer. This study highlights the applications of single‐atom‐coordinated nanotherapeutics in sonothermal–catalytic synergistic therapy, which may create new opportunities in biomedical research.